Colchicine Promotes Atherosclerotic Plaque Stability via the Notch3-dependent Modulation of Smooth Muscle Cell Phenotype

Abstract

Atherosclerosis, a chronic inflammatory disease, leads to severe cardiovascular events such as myocardial infarctions and strokes, primarily due to unstable plaque rupture. Smooth muscle cell (SMC) phenotypes are critical for plaque stability, with destabilisation linked to adverse SMC transdifferentiation and the loss of ACTA2+ SMC-derived cells in the fibrous cap. Despite this, no therapies specifically target SMC phenotypic modulation. Colchicine, an anti-inflammatory drug, has shown promise in reducing cardiovascular risks and stabilising plaques. However, its effects on non-immune cells, particularly SMCs, remain unclear.

This thesis investigates colchicine’s role in modulating SMC phenotypes and plaque stability. Using a hypercholesterolemic Apoe-/- mouse model and SMC lineage tracing, prevention and regression models were established. Histological and immunostaining techniques analysed plaque stability and cellular composition. In vitro experiments on human aortic SMCs, coupled with bulk RNA-Seq, identified relevant signalling pathways, which were further validated in vivo using Apoe-/- Notch3-/- mice.

Key results demonstrate that colchicine reduces plaque formation and promotes regression in advanced plaques by inducing a protective ACTA2+ myofibroblast-like SMC phenotype, enhancing fibrous cap thickness. RNA-Seq and in vitro studies revealed that colchicine reactivates SMC contractile gene expression via TGFβ and Notch signalling pathways. Notch3 deletion impaired fibrous cap stability and reduced colchicine’s efficacy, underscoring Notch3’s pivotal role.

In conclusion, colchicine stabilises plaques by modulating SMC phenotypes through Notch3-dependent mechanisms, highlighting its therapeutic potential for atherosclerosis management. These findings provide a foundation for targeting SMC phenotypes in future therapeutic strategies.